Purpose The aim of this work is to implement real-time 3D MR thermometry for high intensity focused ultrasound (HIFU) monitoring. Methods Volumetric MR thermometry was implemented based on a 3D echo-shifted sequence with short TR to improve temperature sensitivity. The 3D acquisition was accelerated in two phase encoding directions with controlled aliasing in volumetric parallel imaging (CAIPIRINHA)

Minimal residual disease (MRD) in chronic lymphocytic leukemia (CLL) has prognostic and predictive significance. One of the approaches to detect MRD by flow cytometry (FC) is the use of dry antibody reagents such as DuraClone® RE CLB (Beckman Coulter—BC). The aim of this study was to evaluate the performance of the DuraClone® RE CLB in detecting MRD in CLL compared to liquid reagents.

The American Society for Clinical Investigation has selected renowned lupus researcher and rheumatologist Judith James for the 2020 Stanley J. Korsmeyer Award, which is given annually in recognition of scientific excellence and outstanding mentorship of future researchers. Dr. James, member and chair of the Oklahoma Medical Research Foundation and Professor of Medicine at the University of Oklahoma

As of early 2020, humanity is confronting a pandemic in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 causes coronavirus disease, abbreviated as COVID-19. At the time of this writing, SARS-CoV-2 is spreading in multiple countries, threatening a pandemic that will affect billions of people. This virus appears to be a new human pathogen. Currently there are no vaccines, monoclonal

During the past 20 years, integrative medicine centers that promote the use of alternative therapies were established in more than 70 medical and nursing schools. A survey of hospital websites and interviews with physicians, hospital administrators, and staff revealed that 15 research-intensive medical schools in the United States provide alternative therapies in their integrative medicine centers

In spite of the recent approval of new promising targeted therapies, the clinical outcome of patients with acute myeloid leukemia (AML) remains suboptimal, prompting the search for additional and synergistic therapeutic rationales. It is increasingly evident that the bone marrow immune environment of AML patients is profoundly altered, contributing to the severity of the disease but also providing

Multiple myeloma (MM), a bone marrow–resident hematological malignancy of plasma cells, has remained largely incurable despite dramatic improvements in patient outcomes in the era of myeloma-targeted and immunomodulatory agents. It has recently become clear that T cells from MM patients are able to recognize and eliminate myeloma, although this is subverted in the majority of patients who eventually

Lymphoid malignancies typically promote an infiltrate of immune cells at sites involved by the disease. While some of the immune cells present in lymphoma have effector function, the immune system is unable to eradicate the malignant clone. Therapies that optimize immune function therefore have the potential to improve the outcome of lymphoma patients. In this Review, we discuss immunologic approaches

Cellular therapy for hematologic malignancies is a rapidly evolving field, with new iterations of novel constructs being developed at a rapid pace. Since the initial reports of chimeric antigen receptor T cell (CAR T cell)success in CD19+ B cell malignancies, multiple clinical trials of CAR T cell therapy directed to CD19 have led to the approval of this therapy by the FDA and the European Medicines

Hematological malignancies have long been at the forefront of the development of novel immune-based treatment strategies. The earliest successful efforts originated from the extensive body of work in the field of allogeneic hematopoietic stem cell transplantation. These efforts laid the foundation for the recent exciting era of cancer immunotherapy, which includes immune checkpoint blockade, personal

The cardiomyopathy of Duchenne muscular dystrophy (DMD) is an important cause of morbidity and mortality in affected males with this dreaded muscle disease. Previous studies have implicated changes in expression and subcellular localization of connexin-43 (Cx43), the major ventricular gap junction protein, in DMD cardiomyopathy. In this issue of the JCI, Himelman et al. explore how hypophosphorylation

Currently, the incidence of HIV infection exceeds the death rate from HIV, and as a result, the prevalence of individuals living with the infection continues to increase. A critical limitation preventing the development of curative strategies is the lack of knowledge regarding mechanisms that allow HIV-infected cells to persist in individuals during combination antiviral therapy (ART). In this issue

Parathyroid hormone (PTH) has complex effects on bone, including stimulating bone formation and regulating the hematopoietic stem cell (HSC) niche. In the current issue of the JCI, Li et al. demonstrated that the microbiome, through the production of short-chain fatty acids and in particular, butyrate, is necessary for the ability of PTH to increase osteoblast numbers and stimulate bone formation.

Tregs require specific epigenetic signatures to induce and maintain their suppressive function in the context of inflammation and cancer surveillance. In this issue of the JCI, Xiong and colleagues identify a critical role for the epigenetic repressor REST corepressor 1 (CoREST) in promoting Treg suppressive transcriptional and functional programs. Pharmacologic inhibition and genetic loss of CoREST

β-Amyloid aggregates found in brain plaques are viewed as triggers of cytotoxicity and neuroinflammation in Alzheimer disease (AD). However, the main β-amyloid (Aβ) species and what imbues the aggregates with such toxic potential are still not yet understood. In this issue of the JCI, Roy et al. show that Aβ complexed with nucleic acids triggers an antiviral type I interferon response in neuroglia

Chronic graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic cell transplantation that resembles autoimmunity, with unclear pathogenesis and few effective therapeutic options. In this issue of the JCI, Dertschnig et al. used mouse models to investigate the basis of T cell autoreactivity following GVHD. Notably, GVHD caused irreversible damage to a population of tolerogenic

Tumor-associated macrophages (TAMs) represent the most abundant hematopoietic cell type in the solid tumor microenvironment. TAMs drive T cell inhibition, promote angiogenesis, and produce tumor growth factors. Although they can paradoxically exert antitumor activity and prime protective immunity, the pathways driving this phenotype remain unclear. In this issue of the JCI, Liu and colleagues identified

Cystic fibrosis (CF) is a multisystem disorder, but progressive inflammatory lung disease causes the greatest burden of morbidity and death. Recent translational and mechanistic studies of samples from patients, and observations in animal models, indicate that platelets may drive lung injury and contribute to dysregulated host defense in CF lung disease. In this issue of the JCI, Ortiz-Muñoz and Yu

The incidence of human papillomavirus–positive (HPV+) head and neck squamous cell carcinoma (HNSCC) has surpassed that of cervical cancer and is projected to increase rapidly until 2060. The coevolution of HPV with transforming epithelial cells leads to the shutdown of host immune detection. Targeting proximal viral nucleic acid–sensing machinery is an evolutionarily conserved strategy among viruses

Loss of androgen receptor (AR) signaling dependence occurs in approximately 15%-20% of advanced treatment-resistant prostate cancers, and this may manifest clinically as transformation from a prostate adenocarcinoma histology to a castration-resistant neuroendocrine prostate cancer (CRPC-NE). The diagnosis of CRPC-NE currently relies on a metastatic tumor biopsy, which is invasive for patients and

BACKGROUND. Undifferentiated systemic autoinflammatory diseases (USAIDs) present diagnostic and therapeutic challenges. Chronic interferon (IFN) signaling and cytokine dysregulation may identify diseases with available targeted treatments.

Protein arginine methyltransferase 5 (PRMT5) catalyzes symmetric dimethylation (SDM) of arginine, a posttranslational modification involved in oncogenesis and embryonic development. However, the role and mechanisms by which PRMT5 modulates Th cell polarization and autoimmune disease have not yet been elucidated. Here, we found that PRMT5 promoted SREBP1 SDM and the induction of cholesterol biosynthetic

BACKGROUND. Understanding HIV dynamics across the human body is important for cure efforts. This goal has been hampered by technical difficulties and the challenge of obtaining fresh tissues.

Aberrant expression of the cardiac gap junction protein connexin-43 (Cx43) has been suggested as playing a role in the development of cardiac disease in the mdx mouse model of Duchenne muscular dystrophy (DMD); however, a mechanistic understanding of this association is lacking. Here, we identified a reduction of phosphorylation of Cx43 serines S325/S328/S330 in human and mouse DMD hearts. We hypothesized

Deficits in social interaction (SI) are a core symptom of autism spectrum disorders (ASDs); however, treatments for social deficits are notably lacking. Elucidating brain circuits and neuromodulatory signaling systems that regulate sociability could facilitate a deeper understanding of ASD pathophysiology and reveal novel treatments for ASDs. Here we found that in vivo optogenetic activation of the

The genomics of primary prostate cancer differ from those of metastatic castration-resistant prostate cancer (mCRPC). We studied genomic aberrations in primary prostate cancer biopsies from patients who developed mCRPC, also studying matching, same-patient, diagnostic, and mCRPC biopsies following treatment. We profiled 470 treatment-naive prostate cancer diagnostic biopsies and, for 61 cases, mCRPC

Oncogenic KRAS is a major driver in lung adenocarcinoma (LUAD) that has yet to be therapeutically conquered. Here we report that the SLC7A11/glutathione axis displays metabolic synthetic lethality with oncogenic KRAS. Through metabolomics approaches, we found that mutationally activated KRAS strikingly increased intracellular cystine levels and glutathione biosynthesis. SLC7A11, a cystine/glutamate

Parathyroid hormone (PTH) is a critical regulator of skeletal development that promotes both bone formation and bone resorption. Using microbiota depletion by wide-spectrum antibiotics and germ-free (GF) female mice, we showed that the microbiota was required for PTH to stimulate bone formation and increase bone mass. Microbiota depletion lowered butyrate levels, a metabolite responsible for gut-bone

Recent findings have shown that inhibitors targeting bromodomain and extraterminal domain (BET) proteins, such as the small molecule JQ1, are potent growth inhibitors of many cancers and hold promise for cancer therapy. However, some reports have also revealed that JQ1 can activate additional oncogenic pathways and may affect epithelial-to-mesenchymal transition (EMT). Therefore, it is important to

Bruton tyrosine kinase (BTK) is present in a wide variety of cells and may thus have important non–B cell functions. Here, we explored the function of this kinase in macrophages with studies of its regulation of the NLR family, pyrin domain–containing 3 (NLRP3) inflammasome. We found that bone marrow–derived macrophages (BMDMs) from BTK-deficient mice or monocytes from patients with X-linked agammaglobulinemia

A better understanding of all immune components involved in protecting against Mycobacterium tuberculosis infection is urgently needed to inform strategies for novel immunotherapy and tuberculosis (TB) vaccine development. Although cell-mediated immunity is critical, increasing evidence supports that antibodies also have a protective role against TB. Yet knowledge of protective antigens is limited

Peptide MHC class II-based (pMHCII-based) nanomedicines trigger the formation of multicellular regulatory networks by reprogramming autoantigen-experienced CD4+ T cells into autoimmune disease-suppressing T regulatory type 1 (TR1) cells. We have shown that pMHCII-based nanomedicines displaying liver autoimmune disease-relevant yet ubiquitously expressed antigens can blunt various liver autoimmune disorders

Foxp3+ Tregs are key to immune homeostasis, but the contributions of various large, multiprotein complexes that regulate gene expression remain unexplored. We analyzed the role in Tregs of the evolutionarily conserved CoREST complex, consisting of a scaffolding protein, Rcor1 or Rcor2, plus Hdac1 or Hdac2 and Lsd1 enzymes. Rcor1, Rcor2, and Lsd1 were physically associated with Foxp3, and mice with

Cancer-related anemia is present in more than 60% of newly diagnosed cancer patients and is associated with substantial morbidity and high medical costs. Drugs that enhance erythropoiesis are urgently required to decrease transfusion rates and improve quality of life. Clinical studies have observed an unexpected improvement in hemoglobin and RBC transfusion-independence in patients with acute myeloid

BACKGROUND. Residual C-peptide is detected in many people for years following the diagnosis of type 1 diabetes; however, the physiologic significance of low levels of detectable C-peptide is not known.

Spondyloarthritis (SpA) represents a family of inflammatory diseases of the spine and peripheral joints. Ankylosing spondylitis (AS) is the prototypic form of SpA in which progressive disease can lead to fusion of the spine. Therapeutically, knowledge of type 3 immunity has translated into the development of IL-23– and IL-17A–blocking antibodies for the treatment of SpA. Despite being able to provide

Few therapies are currently available for patients with KRAS-driven cancers, highlighting the need to identify new molecular targets that modulate central downstream effector pathways. Here we found that the microRNA (miRNA) cluster including miR181ab1 is a key modulator of KRAS-driven oncogenesis. Ablation of Mir181ab1 in genetically engineered mouse models of Kras-driven lung and pancreatic cancer

Acute graft-versus-host disease (GVHD) is initially triggered by alloreactive T cells, which damage peripheral tissues and lymphoid organs. Subsequent transition to chronic GVHD involves the emergence of autoimmunity although the underlying mechanisms driving this process are unclear. Here, we tested the hypothesis that acute GVHD blocks peripheral tolerance of autoreactive T cells by impairing lymph

Type I interferon (IFN) is a key cytokine that curbs viral infection and cell malignancy. Previously, we have demonstrated a potent IFN immunogenicity of nucleic acid (NA)-containing amyloid fibrils in the periphery. Here, we investigated whether IFN is associated with β-amyloidosis inside the brain and contributes to neuropathology. An IFN-stimulated gene (ISG) signature was detected in the brains

Visceral adipose tissue plays a critical role in numerous diseases. While imaging studies often show adipose involvement in abdominal diseases, their outcomes may vary from being a mild self limited illness to one with systemic inflammation and organ failure. We therefore compared the pattern of visceral adipose injury during acute pancreatitis and acute diverticulitis to determine its role in organ

The major risk factor for kidney stone disease is idiopathic hypercalciuria. Recent evidence implicates a role for defective calcium reabsorption in the renal proximal tubule. We hypothesized that claudin-2, a paracellular cation channel protein, mediates proximal tubule calcium reabsorption. We found that claudin-2–null mice have hypercalciuria due to a primary defect in renal tubule calcium transport

Induction of the inflammasome protein cryopyrin (NLRP3) in visceral adipose tissue (VAT) promotes release of the pro-inflammatory cytokine interleukin-1β (IL1β) in obesity. While this mechanism contributes to peripheral metabolic dysfunction, effects on the brain remain unexplored. These studies investigated whether visceral adipose NLRP3 impairs cognition by activating microglial interleukin-1 receptor

Angiopoietin-2 (Ang2), a ligand of the endothelial Tie2 tyrosine kinase, is involved in vascular inflammation and leakage in critically ill patients. However, the role of Ang2 in demyelinating central nervous system (CNS) autoimmune diseases is unknown. Here, we report that Ang2 is critically involved in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a rodent model of multiple

Tumor DNA circulates in the plasma of cancer patients admixed with DNA from noncancerous cells. The genomic landscape of plasma DNA has been characterized in metastatic castration-resistant prostate cancer (mCRPC) but the plasma methylome has not been extensively explored. Here, we performed next-generation sequencing (NGS) on plasma DNA with and without bisulfite treatment from mCRPC patients receiving

Meal ingestion increases body temperature in multiple species, an effect that is blunted by obesity. However, the mechanisms responsible for these phenomena remain incompletely understood. Here we show that refeeding increases plasma leptin concentrations approximately 8-fold in 48-hour-fasted lean rats, and this normalization of plasma leptin concentrations stimulates adrenomedullary catecholamine

Tyrosine kinase domain (TKD) mutations contribute to acquired resistance to FMS-like tyrosine kinase 3 (FLT3) inhibitors used to treat FLT3-mutant acute myeloid leukemia (AML). We report a cocrystal structure of FLT3 with a type I inhibitor, NCGC1481, that retained potent binding and activity against FLT3 TKD and gatekeeper mutations. Relative to the current generation of advanced FLT3 inhibitors,

After trauma, regeneration of adult CNS axons is abortive causing devastating neurologic deficits. Despite progress in rehabilitative care, there is no effective treatment stimulating axon growth following injury. Using models with different regenerative capacities, followed by gain- and loss-of-function analysis, we identified profilin1 (Pfn1) as a coordinator of actin and microtubules (MTs), powering

Cystic fibrosis (CF) lung disease is characterized by an inflammatory response that can lead to terminal respiratory failure. The cystic fibrosis transmembrane regulator (CFTR) is mutated in CF and we hypothesized that dysfunctional CFTR in platelets, which are key participants in immune responses, is a central determinant of CF inflammation. We found that deletion of CFTR in platelets produced exaggerated

Inherited retinal degenerations (IRDs) are characterized by the progressive loss of photoreceptors and represent one of the most prevalent causes of blindness among working-age populations. Cyclic nucleotide dysregulation is a common pathological feature linked to numerous forms of IRD, yet the precise mechanisms through which this contributes to photoreceptor death remain elusive. Here we demonstrate

BACKGROUND. HBV-related acute-on-chronic liver failure (HBV-ACLF) is hallmarked by high short-term mortality rates, calling for accurate prognostic biomarkers for initial risk stratification.

Macrophages have been linked to tumor initiation, progression, metastasis and treatment resistance. However, the transcriptional regulation of macrophages driving the pro-tumor function remains elusive. Here, we demonstrate that the transcription factor c-Maf is a critical controller for immunosuppressive macrophage polarization and function in cancer. c-Maf controls many M2-related genes and has direct

Despite the effective clinical use of steroids for the treatment of Diamond Blackfan anemia (DBA), the mechanistic bases via which glucocorticoids regulate human erythropoiesis remain poorly understood. Here, we report that the sensitivity of erythroid differentiation to dexamethasone (Dex) is dependent on the developmental origin of human CD34+ progenitor cells, specifically increasing the expansion

While the Western-diet and dysbiosis are the most prominent environmental factors associated with inflammatory bowel diseases (IBDs), the corresponding host factors and cellular mechanisms remain poorly defined. Here we report that the TSC1-mTOR pathway in the gut epithelium represents a metabolic and innate immune checkpoint for intestinal dysfunction and inflammation. mTOR hyperactivation triggered

Severe alcoholic hepatitis (SAH) is a deadly liver disease without an effective medical therapy. Although SAH mortality is known to correlate with hepatic accumulation of immature liver cells, why this occurs, and how it causes death is unclear. Here, we demonstrated that expression of epithelial splicing regulatory protein-2 (ESRP2), an RNA splicing factor that maintains the non-proliferative, mature

The value of contrast-enhanced ultrasound (CEUS) in differentiating between renal cell carcinoma (RCC) and angiomyolipoma (AML) was analyzed. The purpose of this study was to identify the independent indicators of CEUS for predicting RCC. A total of 172 renal tumors (150 RCCs, 22 AMLs) in 165 patients underwent conventional ultrasound (CUS) and CEUS examinations before radical or partial nephrectomy

Introduction Multiple sclerosis (MS) is a central nervous system disorder that may eventually affect its function. The clinical standard for MS severity is based on a clinical scale, which lacks lesion specific information. Magnetic resonance imaging of MS faces the challenge of myelin specificity, and in this work a new method inhomogeneous magnetization transfer (ihMT) is investigated as new biomarker